In a phase I/II study mitoxantrone and etoposide, in combination with cytarabine, were given to 26 patients with refractory, relapsed, and previously untreated acute nonlymphocytic leukemia. Therapy consisted of mitoxantrone 12 mg/m2/day for 3 days, etoposide 100 mg/m2/day and cytarabine 1 g/m2 twice a day for 5 days. A total of 14 complete remissions (CR, 54%) were noted. Among refractory patients 5 of 10 achieved a CR as compared to 5 of 6 in the previously untreated group. A favorable response was also seen in patients with late relapse off treatment (3/4 CR) while patients relapsing on therapy did worse (1/6 CR). The results suggest a high antileukemic activity and a moderate toxicity for this drug combination.